The Peter Attia Drive - #244 ‒ The history of the cell, cell therapy, gene therapy, and more ｜ Siddhartha Mukherjee

00:00:00.000 Hey, everyone. Welcome to the drive podcast. I'm your host, Peter Atiyah. This podcast,

00:00:15.500 my website, and my weekly newsletter all focus on the goal of translating the science of longevity

00:00:19.820 into something accessible for everyone. Our goal is to provide the best content in health and

00:00:24.780 wellness, full stop. And we've assembled a great team of analysts to make this happen.

00:00:28.900 If you enjoy this podcast, we've created a membership program that brings you far more

00:00:33.320 in-depth content. If you want to take your knowledge of this space to the next level,

00:00:36.920 at the end of this episode, I'll explain what those benefits are. Or if you want to learn more now,

00:00:41.760 head over to peteratiyahmd.com forward slash subscribe. Now, without further delay, here's

00:00:48.100 today's episode. My guest this week is Siddhartha Mukherjee. Sid was a previous guest on episode

00:00:56.520 number 32, way back, boy, December 2018, I believe. Sid is a cancer researcher and a cancer

00:01:04.600 physician, a practicing oncologist. He's an assistant professor of medicine at Columbia University

00:01:08.800 and a staff cancer physician at the Columbia University NYU Presbyterian Hospital. He also

00:01:15.060 happens to be a luminary author. He's written four books, The Emperor of All Maladies, The Laws of

00:01:21.080 Medicine, The Gene, and his most recent book, The Song of the Cell, An Exploration of Medicine

00:01:26.520 and the New Human. In my first podcast with Sid, we mostly discussed The Emperor of All Maladies,

00:01:33.300 The Biography of Cancer, a book that won him the Pulitzer Prize. In this podcast, we primarily discuss

00:01:40.080 his most recent book, The Song of the Cell. This is a book that I just devoured. And I wouldn't have

00:01:46.240 thought I could find a book about the history of the cell so interesting. But as you can tell by

00:01:51.980 the fact that we're doing this podcast, I clearly did. We talk about so many things that I think to

00:01:57.180 sort of try to do it in the intro would do it no justice. But we go everything really from the

00:02:00.760 evolutionary drive to go from single cell to multi-cell organisms, all the way up to cell therapy,

00:02:06.660 gene therapy, CRISPR, of course, all these things. So we talk a lot about Sid's writing process as well,

00:02:11.600 given that he's such a prolific writer, and frankly, some very personal things, including

00:02:16.300 his decision to open up about his own depression in his writing. So it's always a pleasure for me

00:02:21.340 to sit down and talk with Sid, especially when we can do it like this and record it. So without

00:02:24.880 further delay, please enjoy my conversation with Sid Mukherjee.

00:02:32.920 Hey, Sid. So great to see you again. It's been a long time since we've seen each other in person.

00:02:37.200 The last time we sat down for one of these, of course, it was in person and we didn't have video.

00:02:40.540 And now we've got video, but we're in a different time zone. Congratulations on the

00:02:44.940 success of your most recent book. For folks listening or viewing, give us a sense of where

00:02:51.080 this book fits into the prior work. We talked at great length about one of your books, The Emperor

00:02:56.200 of All Maladies, but there was a book that followed that. And then of course, there's this. So maybe put

00:03:00.240 this in the context of those books. This is part of a trilogy and possibly a quartet that I'm

00:03:05.860 working on broadly called the Life Series. And the attempts of these books is to try to explain

00:03:11.500 and understand how we understand life and how we're manipulating life, living things,

00:03:17.920 obviously, particularly humans. In an odd way, the place to begin to some extent, the trilogy

00:03:24.100 right now. So the first book, The Emperor of All Maladies, the second, The Gene, and now The Song of

00:03:29.080 All Maladies, would be to probably start with the gene. Now the gene being the least unit or the

00:03:35.040 smallest unit of information. And then realize as you end the gene, that genes which are encoded in

00:03:42.400 DNA, the molecule DNA, are lifeless. They don't have any autonomous life. A gene is just a molecule,

00:03:49.820 it's a chemical. And it's the cell that brings it to life. And without the cell, there would be

00:03:55.860 nothing. All of that code would be useless. I liken the human genome, or any genome, to a score

00:04:02.940 of music. But a score is lifeless. There's no music in a score. It's just a code. You need a musician

00:04:09.080 to bring it to life. And the cell is that musician. Hence the title of the book, The Song of the Cell.

00:04:14.880 The cell brings it to life. So the second book, to some extent, is The Cell. And then the third book,

00:04:21.040 bizarrely enough, is the first book. It's sort of like Star Wars, the prequel to the sequel to

00:04:25.780 the prequel, where you learn about what happens when cells become aberrant. So that would be one

00:04:31.820 way to read the series of books. Start with the gene, move on to the second unit, which is the cell,

00:04:36.820 and finally end up with the dysfunctional aberrant cell and what happens to it when its genes go haywire.

00:04:44.000 A completely different way would be to read them as they appeared. And the reason behind that is that

00:04:49.200 they progressively go downwards. I mean, the first book was, of course, A History of Cancer

00:04:54.160 and Cancer Therapy, they progressively go downwards and delve deeper and deeper into mysteries of that

00:05:02.320 history, you know, missing pieces. What did we not understand about cancer? Obviously, genes and

00:05:08.500 genetics. What did we not understand about cancer in terms of its cell biology when the cancer genome

00:05:15.720 atlas was, for instance, completed? And what do we understand now? So they can also be read

00:05:21.940 chronologically from the first to the third, you would get a different kind of story. And that's

00:05:26.620 what's interesting about it. You can read it by the way. It's possible that my question slash

00:05:31.720 statement here is tainted by a bit of recency bias because I read them in order. And of course,

00:05:36.280 I've just finished reading The Cell because we decided on a very last minute basis, we were going

00:05:40.840 to try to do this podcast. Last minute for the way my podcast works, which is months of preparation.

00:05:44.900 So, you know, I was reading the book in the period of the last week and a half, which I enjoyed

00:05:49.740 immensely. But here's the thing. I felt more surprised and in awe of the characters in this

00:05:59.620 book than the previous books. And that might sound crazy because you'd think, God, decoding the human

00:06:05.200 genome, what a Herculean feat. But in many ways, the characters of this story blew my mind even more

00:06:11.920 because of the time and the era in which they had to do their science. There were fewer tools at

00:06:18.560 their disposal. Does that statement surprise you or how does that resonate with you?

00:06:23.120 It's not surprising. It's because the characters in this book are enunciating things that are,

00:06:30.540 I think, very fundamental. If you take, for instance, a comparison, if you were to do a historical

00:06:36.220 comparison with the history of genetics, in the scientific world, you would start with Mendel,

00:06:40.800 Greger Mendel, of course, being the pioneer here. And then there's an enormous period of silence

00:06:46.920 that follows Mendel, almost 40 years, in which basically nothing happens. And then, you know,

00:06:52.860 his work is picked up by other people, ultimately picked up by folks like Thomas Morgan and others.

00:06:59.320 But for a long period of time, nothing happens and nothing's relevant. What you see in this book is

00:07:04.540 very different because you see a sort of continuation of development. So once the microscope is invented

00:07:12.100 in the 17th century, you see from the 17th century a kind of gradual blossoming of the science,

00:07:20.080 ultimately ending up with someone like Rudolf Virchow, who can make really audacious statements that

00:07:26.280 are missing in the history of genetics until much later. The audacious statement that Virchow makes is

00:07:32.140 every function that we carry out, regardless of its origin or regardless of what that function is,

00:07:39.180 is a consequence of cellular physiology. We ourselves and everything that we do is cellular,

00:07:45.280 is a consequence of something happening in some cell. This conversation is a consequence of something

00:07:49.900 happening in some cell. So that's one piece, that's statement one. And then you get the other

00:07:54.760 converse statement, which is equally audacious, in which he says that every illness is the consequence

00:08:01.360 of some cell behaving incorrectly. And these statements are made in the mid to late 19th century.

00:08:07.140 They're in fact almost contemporaneous with Mendel. So you have enormous sets of leaps in cell biology,

00:08:14.500 which is why this book might feel that these characters are doing things while genetics is

00:08:21.220 still plodding its way, trying to understand Mendel's first very important paper. And there's a

00:08:27.820 remarkable 40 years of silence, whereas in cell biology, there isn't that 40 years of silence.

00:08:33.540 And I think also, maybe we take it for granted sometimes today, but the ingenuity that was

00:08:39.020 necessary to even build the tool to permit the visualization. I mean, we just glossed over the

00:08:43.500 fact that in the 17th century, we're putting together microscopes, but you actually describe in

00:08:47.960 some detail what the process is like to grind the glass, to create the lens, to even have the window

00:08:53.700 into this otherwise microscopic and invisible to our eye piece of physiology.

00:08:58.540 It's an incredible, I tried to make one myself. I tried to make one of Lewin-Hook's microscopes.

00:09:04.820 And I can tell you, Peter, it was not an easy task. It was a disaster. And he made 500 of them.

00:09:10.900 These are single lens microscopes, and they're about this big. It's about the size of half a sheet of

00:09:16.900 paper. And the lens is smaller than the size of your eyeball. So you have this sense in which you

00:09:24.300 have an enormous amount of labor of love put into making this thing that's mounted with tiny screws

00:09:31.240 and tiny little apertures, so that when you look through your eye, through the lens in a droplet of

00:09:37.720 water, you can actually see these microscopic forms. So there's an enormous sense of wonder about how

00:09:45.260 people even began to see these and how they found them and what the consequences of that finding

00:09:51.700 were and are. People who listen to my podcast are probably used to an idea that I talk about.

00:09:57.780 And you have come across this now, Sid, because you were kind enough to be one of the people who

00:10:01.260 read my book. But I talk about this transition from medicine 1.0 to medicine 2.0. And then,

00:10:06.160 of course, where I hope we're going is the transition from 2.0 to 3.0. And I typically talk

00:10:10.720 about medicine 1.0 to 2.0 as two big events happened. And they weren't momentary events,

00:10:16.260 they were transitions of process. One was, of course, the way we changed the way we thought,

00:10:20.080 right? So it was the scientific revolution. So once we introduced the scientific method,

00:10:24.880 late 15th century, we had a new way of thinking about observation and hypothesis. And all of a sudden,

00:10:31.420 the idea of bad humors and all that stuff sort of went away. But really, the big moment became germ

00:10:37.720 theory. Once we understood microbial agents and that we had a way to treat them, we really

00:10:44.280 leapfrogged into the era of modern medicine. And if you look at the mortality rates as a result of

00:10:49.520 that, it's outstanding. I mean, there has been no bigger reduction in human mortality than the

00:10:55.300 reduction of death that comes from infectious diseases. What I had never really thought of until

00:11:00.080 I read your book was that couldn't have happened without this deep understanding of the cell. I mean,

00:11:05.300 it's obvious when I say it that way, but in effect, this book describes how medicine went

00:11:12.000 from effectively witchcraft into where we are today. We're going to talk about this in more

00:11:17.140 detail, by the way, but does that make sense to you? Oh, absolutely. It makes sense to me in the

00:11:21.320 sense that it makes sense because the introduction of being able to ultimately see germs and connect

00:11:29.880 germ theory with human disease, as you say, took medicine from witchcraft to the modern era.

00:11:36.360 Think of any procedure, childbirth, any surgical procedure, anything that we do, and think of the

00:11:42.480 effect of antibiotics on that procedure and think of how important it is that these antibiotics are

00:11:47.800 now available and the lifesave. I mean, just childbirth alone, the capacity of saving lives through

00:11:53.660 antibiotics has been enormous and transformative in terms of, as you say, moving medicine from witchcraft

00:11:59.780 itself. What's astonishing in the piece that I write about microbial biology and the discovery

00:12:05.040 of microbes, Peter, is that microbes were imagined in the abstract long before they were seen. So

00:12:13.520 what's interesting is people like Lister, the great surgeon who began to sterilize his instruments,

00:12:20.580 folks like Semmelweis, and I have a small biography of him in the book, almost ignored by medical history

00:12:27.380 now. But Semmelweis discovered that doctors were transmitting microbes.

00:12:32.640 Tell the story. I have it in my book. You have it in your book. I'm really glad that more and more

00:12:37.700 people are writing about him because it always breaks my heart when someone dies without their due.

00:12:43.220 And Semmelweis is the example of that. And it's a heartbreaking story, but it's a remarkable example

00:12:48.800 of this transition. So Semmelweis was a junior obstetrician in Vienna. It's important that he was

00:12:56.560 so junior. And he made a very important and incredibly important discovery. So Semmelweis was

00:13:04.780 delivering children. And there were two maternity wards, ward one and ward two. And this is why it's

00:13:10.380 important in medicine, I think, to listen to your patients. You know, the famous adage in medicine is

00:13:15.580 the most important question that you ever ask in medicine, when you're trying to diagnose a patient

00:13:21.480 is to ask the patient, what do you think the problem is? And it's the one we forget the most,

00:13:26.060 right? Doctors never ask that question. But usually the patient will tell you. They'll say, you know,

00:13:30.980 I think I have an infection in my lungs, or I think I'm depressed because of X or Y reason,

00:13:37.160 because I lost my father. So Semmelweis learned to ask people of a bizarre aberration that was going on,

00:13:44.640 which is that in ward one, the maternal mortality rates from childbirth were astronomically high,

00:13:52.000 whereas in ward two, same people, same women coming in were much lower. And he knew this because,

00:13:59.100 you know, at least the story goes, whether it's apocryphal or not, that in ward one, mothers would

00:14:04.920 beg to be admitted into the safer ward, while they would beg not to be admitted, where they would have

00:14:11.060 a 30% mortality rate, or a 20% mortality rate, one out of five women. I mean, it's an incredible number 1.00

00:14:17.320 if you think about it. So Semmelweis began to ask the question, why? And he looked at all sorts of

00:14:22.760 variables. He was sort of a classical epidemiologist. So he looked at all sorts of variables. And the

00:14:29.000 variable that he found was that in the first ward, where there was a high mortality rate, it was run

00:14:34.360 by doctors. And these doctors, he figured out, were running between autopsy rooms, doing autopsies on

00:14:42.440 probably the very patients that they had killed, and then running, and then without cleaning their

00:14:47.160 hands, delivering babies, essentially examining patients, delivering babies, etc. Ward two, on the

00:14:53.500 other hand, was run by nurses. Nurses were not doing autopsies, not touching any decaying or dead

00:15:00.040 material. And there was no mortality. So Semmelweis made the hypothesis, again, remember, this is a

00:15:07.220 junior obstetrician in Vienna, that what doctors were doing is they were transferring, and these are

00:15:13.280 his words, some material substance from the decaying, decomposing dead bodies that they had autopsied

00:15:20.940 into the bodies of the women that they were examining internally, and thereby transmitting that

00:15:27.580 material substance. And that material substance was the source of the putrefaction or the infection

00:15:33.920 that these women were getting. And he insisted that the doctors wash their hands with a diluted 0.99

00:15:39.440 version of bleach. And he saw that suddenly, now the mortality rate plummeted. And so he made this

00:15:45.480 argument. Now, remember, he didn't have a microscope. It is all in the abstract. But he made this argument

00:15:51.400 that this material substance was responsible for what was then called childbed fever or maternal

00:15:59.180 infections. And the transfer of the material substance could be removed by handwashing. So in

00:16:06.360 the abstract sense, he had basically founded germ theory. Completely prescient.

00:16:11.880 Yeah. And the idea of a material substance, that's what's important about it.

00:16:16.380 Right. It wasn't just bad air in a vague sense.

00:16:19.420 It was not bad air. It was not bad humors. It was a material substance. And of course,

00:16:25.200 if he had the capacity to look down the microscope, he would have found out that that material substance

00:16:29.840 was in fact nothing else but germs. And the sad thing, the epilogue to the story is the guy dies

00:16:36.520 in an insane asylum, basically having been ridiculed. That's right. So he's ridiculed. The last thing that

00:16:42.600 the doctors want to do is to admit that they've been infecting other women. So Samuel Weiss is ridiculed,

00:16:48.560 and he's sent off to an insane asylum. And ultimately, he dies impoverished and never vindicated.

00:16:55.840 Medicine is full of these stories. But this is what it was about the book that really captivated

00:17:00.080 me. This thing that I've taken for granted so much of my existence in medicine is what really allowed

00:17:07.000 this leapfrog. And frankly, far more so than the genetic revolution. I mean, we could sit and talk

00:17:12.020 about has the genetic revolution delivered on its promise. In some ways, yes. In some ways, no. We

00:17:17.400 thought whatever it was 22 years ago when the human genome was coded, that was basically going to be

00:17:21.960 an equal leapfrog forward. It turned out not to be. We'll come back to talk about some genetic stuff.

00:17:27.740 But I want to go back to a question that you pose in the book that I had never contemplated,

00:17:34.400 and I have not been able to stop thinking about it, and I love it. Which is,

00:17:37.420 what's the evolutionary drive for multicellular life? We go from these single-cell organisms

00:17:44.780 that have all of their own evolution built into them, and then look at the complexity that we are

00:17:50.360 today. You go through this very elegantly. Let's pause for a second to contemplate single-celled

00:17:56.560 organisms. So they are bacteria, protozoa, yeast, et cetera. They're extraordinarily successful.

00:18:03.200 You can't imagine how successful they are. They live in virtually every environment that you can

00:18:08.440 think of. You know, they live in boiling water. They live in thermal vents. They live in inside

00:18:13.340 volcanoes. They live, I mean, how successful is a single-celled organism? The bizarre question that

00:18:19.060 you should ask is why we exist at all? What is the reason that we have trillions of cells? Why do we

00:18:24.960 exist? Why aren't we all bacteria? And people have been trying to answer the question. And the initial

00:18:30.300 idea in the 80s was that there was a massive leap, evolutionary leap, from single-celled organisms

00:18:37.200 to multicellular organisms. But what's surprising is that if you look at evolutionary history, and if

00:18:43.280 you look at all the evidence from evolutionary history, it turns out that multicellularity evolved

00:18:49.480 from single-celled organisms not once, but independently multiple times. It used to be called a major

00:18:55.760 transition. It actually turns out to be a minor transition. In other words, there was a great

00:19:01.000 evolutionary drive towards becoming multicellular. And you can ask the question then, well, if single-celled

00:19:06.500 organisms are so damn successful, why ever be a multicellular organism? The quick answer is we don't

00:19:12.640 know, but all the evidence suggests that it has to do with several possibilities. The leading possibility

00:19:20.220 is predation. It's much harder for a predator to eat a multicellular organism for several reasons. One

00:19:26.620 of them is that it's bigger. Number two is that it has defense systems. Number three is that it can move

00:19:33.280 away from predators through specialized apparatus. So that's one idea. The other idea is food and

00:19:40.640 resources. Multicellular organisms can access food and resources. And there are other ideas about how

00:19:46.160 multicellular organisms came to exist and essentially conquered the world, as we know. But that said,

00:19:53.800 single-celled organisms are still the champions. We are just a minor fixture in the world. If you took

00:19:59.980 by weight all the single-celled organisms in the world and their diversity, you would be shocked at how

00:20:06.800 successful you still are. Remind us what Ratcliffe's experiments with yeast demonstrated. I had never

00:20:13.080 heard of that experiment before, so I'm reading this like I'm reading a thriller novel.

00:20:17.600 William Ratcliffe is a professor who studies this evolutionary transition from single-celled to

00:20:23.100 multicellular organisms. And he did this, actually, an extraordinary simple experiment. And he just

00:20:27.800 thought about it over Christmas with Travizano, his advisor. He said, well, why don't we just take some

00:20:33.300 yeast and culture them? And we basically allow them to grow. And so, remember, yeast are single-celled

00:20:40.340 organisms. And we just collect the sediment. So, anything that's multicelled is obviously going

00:20:45.380 to sink to the bottom of a flask. We collect the sediment. And then we allow that sediment to grow

00:20:50.380 again in another cycle of evolution. So, this is sort of Darwin in a bottle. So, we allow that to

00:20:55.380 evolve another cycle, collect the sediment, allow that to evolve another cycle. And by about 30 or 40

00:21:01.260 cycles, he found that the yeast had evolved. And this is astonishing. I have pictures of this in the

00:21:06.220 book, into these sort of snowflake-like, multi-fingered, multicellular forms. Really a

00:21:14.240 new organism, a multicellular yeast. And what's interesting about them is that when he let them

00:21:19.180 be by themselves, so no more recollection, no more sedimentation, they continued to propagate as

00:21:25.780 multicellular yeast. So, in other words, he had basically created a new life form, which is

00:21:32.000 multicellular. And what is even more interesting is that when he looked at these multicellular yeast,

00:21:37.480 they started to acquire specialized functions. So, you would imagine that one way that these

00:21:42.840 multicellular yeast could reproduce is that one cell could butt off and create a new multi-fingered, 0.57

00:21:49.320 multicellular yeast. That would be one way that these organisms could reproduce. But that's not how 0.56

00:21:54.220 they reproduce. The way they reproduce is that a specialized series of cells that sit in the middle 0.98

00:22:00.400 of this snowflake, commit a purposeful cellular death. I repeat the word, they commit a purposeful

00:22:08.760 cellular suicide such that this snowflake can break into two parts, two snowflakes, and grow out new

00:22:15.560 fingers. So, this organism has now, evolutionarily speaking, learned. The word learned implies that it

00:22:22.820 has some consciousness, but that's not true. This is just an evolutionary process. It has created a

00:22:28.360 specialized furrow in its middle, where these cells basically can divide into two forms. And what's

00:22:35.960 more is that he's now, Draxler has done many versions of this experiment. He's done it with algae. He's done

00:22:41.800 it with various other organisms. And what he finds is that there's even more specialization. So, these new

00:22:47.800 creatures, that's the only thing I can call them, form little channels to deliver nutrients. They form pores. 0.99

00:22:54.820 They form secondary structures. He's really sort of created a new kind of life. And just by doing

00:23:01.580 nothing, I mean, just by allowing it to evolve naturally. And remember, this is 30, 40 cycles,

00:23:08.620 which may be 60, 80, 90 days. So, you can imagine over the course of several billion years of history,

00:23:16.220 the extraordinary amount of diversity and specialization that could happen in evolution that

00:23:21.920 leads to people like you and me, having trillions of cells, very committed to doing one thing or

00:23:28.260 another thing or many other things. Because my kids, who were five and eight at this point, they're,

00:23:33.540 as you can probably imagine, obsessed with dinosaurs. So, we're nonstop watching every

00:23:38.260 imaginable thing. Paleontologists are the most important people in the world at this point.

00:23:43.060 I can't help but wonder when I watch these recreations of what we assume dinosaurs to have

00:23:47.880 looked like. I mean, at least we know about their size. How did evolution allow something so large

00:23:54.220 to be in existence so many millions of years ago? And are we basically seeing a correction now? In other

00:24:00.580 words, was that just the pendulum swinging too far towards multicellular, where here you have things

00:24:06.760 that can really defend themselves, that can really get away, that can really go after prey, but of course,

00:24:12.040 they're too sensitive to a reduction in food or something like that? Or is that just totally

00:24:17.300 unrelated? And had it not been for volcanic eruptions and things like that, maybe we just

00:24:22.340 wouldn't be here today and dinosaurs would be the sentient higher order creature?

00:24:27.340 A little bit outside my pay rate in some ways. But you know, there's lots of theories. I'm certainly not a

00:24:32.800 paleontologist. So, there are lots of theories about the extinction of dinosaurs. What we do know is that

00:24:38.700 these life forms were also very successful in their environments. The problem was, as many people have

00:24:45.760 hypothesized, that they reached a maximal capacity of size. And smaller mammals or mammal-like creatures

00:24:54.480 became much more adapted or adaptable to the environment. But there are a thousand theories about

00:25:00.280 dinosaur extinction, including changes in the atmosphere, meteors, and various other volcanoes and

00:25:07.600 events, which you can read in most paleontology textbooks.

00:25:11.760 I just wonder if there's something about their size that became their downfall beyond the obvious

00:25:18.060 external factors. And it just made me think of that when I was reading that segment about

00:25:22.600 the fitness of the single cell.

00:25:25.100 There's a beautiful essay, if I remember correctly, by Stephen Gould, where he talks about a natural

00:25:32.520 biophysical limitation on size. And that's because the volume to surface area of any creature reaches a

00:25:41.580 place where the volume to surface area becomes no longer sustainable, because the surface area of a

00:25:48.100 creature is no longer able to deliver the oxygen and the nutrients required for aerobic living.

00:25:56.300 I'd encourage people to read it. I don't remember the name of the essay, but...

00:25:59.980 We'll find it. It has to do with a rhinoceros and what the size limits of creatures can or cannot be.

00:26:07.000 Interesting. So let's go back to something in the book where you talk about the four types of cell

00:26:12.220 therapy. When you spell it out, it sort of makes sense, but I'd never considered this before.

00:26:17.920 I think it's an illustrative framework for people to think about the era of medicine that we live in.

00:26:22.660 So what are these four areas of cellular therapy?

00:26:25.280 I tried to create a typology of the four types of ways in which we could use cells as medicines.

00:26:33.640 The first is the simplest one of all, which is to use a drug or a substance to change the behavior

00:26:38.960 of a cell. So the simplest example would be an antibiotic. You're using a drug to kill

00:26:44.940 a microbial cell while you're sparing normal human cells. That's one. The second one is the transfer of

00:26:52.740 cells from one body to another body without any modification. The simplest example of that would

00:26:58.200 be blood transfusion. So you're transferring red blood cells, platelets, and other cells from one

00:27:03.740 body to another body for therapeutic effect, but you're not essentially changing the cell itself.

00:27:09.380 The third is the use of a cell either transferred or by itself in a dish, in a bioreactor, in a chamber

00:27:17.440 to synthesize something. So I remember I said that DNA is inert. It's a lifeless molecule. If you put it

00:27:23.680 inside a cell in the right context, the right cell in the right context, the cell will start making

00:27:28.140 proteins out of DNA. And those proteins could be very useful. So the insulin, for instance, you can only

00:27:35.140 make insulin in cells or you can, that's how insulin is generally made. Antibodies are made by cells.

00:27:41.880 The antibody receptor that you use in breast cancer is made by cells. So that's a third use. And the

00:27:47.920 fourth and the final is the one that is coming up and now becoming more and more prominent as we move

00:27:53.220 into this new era. And that is the use of a cell where you make a genetic modification in a cell

00:28:00.220 and then either transplant it or use it for a therapeutic reason. So for instance, our T cells,

00:28:08.020 which I'm sure we'll talk about, are examples of genetically modifying T cells and putting them

00:28:14.480 into a human body. I've been doing, as you very well know, a series of experiments on bone marrow

00:28:21.500 transplants in which we genetically modify the bone marrow using CRISPR and other techniques and then

00:28:27.260 transferring them into human bodies and essentially creating genetically engineered cells. People often

00:28:34.280 talk about gene therapy and I always remind them that gene therapy is really cell therapy.

00:28:40.360 If you put the gene in the wrong cell in the wrong place at the wrong time, you get nothing. You get

00:28:45.500 the disaster. So gene therapy is really a mechanism to put a gene inside a cell and that would be the

00:28:52.800 fourth typology, as it were. And then the book goes through elements of these four typologies,

00:28:58.620 examples and elements of these four typologies as medicines.

00:29:01.880 Well, let's touch on a few of them because you and I don't have the ability to sit here for the

00:29:06.820 next three days, which is what it would take to do each of these, their appropriate service.

00:29:11.220 There are a handful that I really want to talk about. So let's talk about the story of Jesse

00:29:15.920 Gelsinger because that is one of the earliest examples of gene therapy in a human. We could talk

00:29:23.420 about what went wrong, but let's use Jesse's story just as much to explain the state of the

00:29:27.920 technology at the time, the vectors, the vehicles, the methods by which genes were transferred. So

00:29:33.760 let's just start with kind of what disease did Jesse have? Why was gene therapy viewed as the

00:29:39.740 solution as opposed to whatever the other three methods would have offered Jesse?

00:29:44.740 So Jesse had a genetic disease. He was a young kid, I think 14, 15 years old, 16 maybe. And I've had a

00:29:52.660 very, very, very moving interview with his father. He had a defect in an enzyme, which is related to

00:29:59.780 the processing of ammonia and ammonia related substances in the body. The idea back then, and we're now

00:30:07.900 talking about 22 years ago. Yeah, it was about 2000. Yeah. At the University of Pennsylvania, the idea was that

00:30:15.520 if they could create a virus, which would then go to Jesse's liver and start making the correct version

00:30:24.520 of the gene, then Jesse's disease would be ameliorated. So they created a virus that they thought was going

00:30:30.700 to be harmless. It was a variant of an adenovirus. And then they genetically modified that adenovirus to

00:30:38.200 now include the corrected version of the gene that Jesse had a problem with. And then they infuse that

00:30:45.500 virus into Jesse's body, hoping that the virus would go and infect because viruses infect cells

00:30:51.120 and deliver its cargo. The cargo would be the corrected gene and thereby correct Jesse's disease.

00:30:57.500 So that was the idea behind that therapy. Let's explain two things before we go on with the story.

00:31:03.940 We didn't say this earlier, so I think it's worth clarifying. We don't really consider viruses in the

00:31:09.840 same category as bacteria, yeast, fungi. Why is that? Do we consider them living things? Are they not

00:31:15.500 living things on their own? I mean, they basically just contain DNA and RNA, but they're sort of

00:31:19.980 parasites in it they need us to replicate? That's right. So viruses are not, they don't meet the

00:31:25.880 criteria of living things. They are essentially a strand of RNA or multiple strands of RNA or DNA

00:31:34.660 that have been packaged usually with an envelope and decorated with some proteins on top. But they,

00:31:41.880 by themselves, they can't reproduce. They can't make copies of themselves, which is one of the

00:31:45.960 reasons that they're not considered living. The only way they can reproduce is they go and attach

00:31:50.460 themselves to cells, let's say to human cells or any other cells. And then they use the reproduction

00:31:58.740 apparatus, the duplication apparatus and the reproduction apparatus and the synthetic apparatus that's present

00:32:06.200 in the cell to make copies of themselves. And once they've made copies of themselves, they bud out of

00:32:12.280 the cell, and then they go and infect more cells and make more copies of themselves and so forth.

00:32:16.920 That's what a virus is. And in Jesse Gutzinger's case, the idea was that this virus would essentially

00:32:22.280 infect his cells. And because the virus was genetically modified, it would insert its genetic payload,

00:32:29.300 which consisted of the normal gene into Jesse's liver cells. The liver cells would now start making the

00:32:35.060 protein that was defective in Jesse's case. This is gene therapy. And then in doing so,

00:32:41.800 it would reverse his relatively mild disease.

00:32:45.780 So what happened then? They used this adenovirus, they injected him, and it went pretty bad pretty quick.

00:32:53.020 Yeah. So a rather terrible thing happened. And again, I have a very moving testimony from his father,

00:32:58.480 which is in the gene, a little bit in this book, but really in the gene, a terrible thing happened.

00:33:03.120 So in retrospect, we think what happened is that Jesse mounted a very vigorous immune response.

00:33:12.160 A virus is a foreign object, a foreign body, and you mount an immune response to it, especially

00:33:17.160 if you, for whatever reason, have been exposed to that virus before. And people now suspect,

00:33:23.560 we don't know for sure, adenoviruses cause common colds, they cause, you know, incirculation. There's a

00:33:30.200 suspicion that Jesse had been exposed to that virus, the wild form of that virus before, perhaps through

00:33:38.140 a common cold or something like that. And his immune system went berserk. Because it was now recognizing

00:33:44.660 not one virus particle, but millions of particles suddenly into his body. His immune system went berserk.

00:33:52.120 And when the immune system goes berserk like that, you basically have terrible consequences because

00:33:57.400 your body is recognizing your cells as foreign, the virus is foreign. It goes on what I call a kind

00:34:03.880 of immune rampage. And that immune rampage can kill you. And unfortunately, Jesse died from the

00:34:10.600 consequences of this very hyperactive, brisk immune response raised against that virus. And in fact,

00:34:17.400 the whole field of gene therapy was frozen for almost a decade as we learned to slowly understand

00:34:25.120 the cause of that death and how we could prevent it in other people.

00:34:29.320 So I think in response, the field said, look, we need to look at slightly more immune protected or

00:34:35.600 privileged sites to dip our toes back in the water. Tell folks a little bit about what's a safer place

00:34:42.140 to maybe consider gene therapy as the field moves closer to that.

00:34:46.440 Well, there are many things that have happened. It's not just safe places. So I'll give you some

00:34:49.940 examples. Again, I'll try to create a typology for you. So one thing you can do is there are safe

00:34:55.100 harbors in the body. By safe harbors, I mean places that the immune system doesn't usually reach

00:35:00.620 easily. The retina turns out to be one of them. There's not a lot of immune cell infiltration into the

00:35:06.620 retina. So you have a chance to use gene therapy. And in fact, there are now several gene therapies

00:35:12.000 that have been approved that allow you to insert or inject viruses so that you can correct a gene

00:35:18.840 that's missing or abnormal in the retina. So that's one place. There's some other places in the body.

00:35:24.380 Turns out the testes is another place, although we've not used that for gene therapy. That's one thing

00:35:29.620 you can do. The other thing you can do is there are new drugs that can dampen down or tack down the

00:35:36.800 immune response. So you can think of the immune response as a dial. What you can do is you can

00:35:41.640 dial the immune response down so that the immune response doesn't respond so briskly to the gene

00:35:48.840 therapy. You can hide the virus. So you can make a virus such that your body has not seen such a virus

00:35:57.000 before. So you can actually use a novel kind of virus that won't raise a brisk immune response.

00:36:02.700 The fourth thing you can do is you can actually give the gene therapy in small doses. It's called

00:36:08.760 hyperfractionation, fractionation being small fractions, so that the immune system doesn't

00:36:14.260 again go berserk, seeing this massive bolus of a dose of virus. So those are some of the strategies,

00:36:21.380 and they've been very successful. So that now the number of deaths from this hyperactive immune

00:36:27.200 response still remain, but they are much, much, much more controlled than in Jesse Gelsinger's times.

00:36:33.720 So you alluded to an example earlier of CAR T-cells. I think it's one of the great successes of cancer

00:36:39.600 when it comes to treating CD19 or B-cell cancers. Let's use that as an example to explain

00:36:45.200 how gene therapy can work in that regard. Well, so CAR T-cells are a very special example

00:36:50.980 of gene therapy. So in a CAR T-cell, what happens is that you extract T-cells from a human being who

00:36:58.240 has cancer. You extract their normal T-cells, and you use gene therapy to weaponize them so that they

00:37:06.200 can attack cells, including cancer cells. So you're essentially turning a T-cell. A T-cell is part of

00:37:13.280 the immune system. Its job is to hunt out and kill foreign cells, including cells that have been

00:37:19.480 infected by viruses or foreign cells that have somehow entered the body. That's their job. That's

00:37:25.000 the job of a T-cell. It's a foreign cell detector built into your body. So now you take that T-cell

00:37:31.440 and weaponize it to recognize the cancer cells as foreign, and then you re-inject them. You grow them

00:37:38.100 in a petri dish in the laboratory, and you re-inject them into the body. And, you know, our laboratory

00:37:43.080 has done a lot of this work. We are now doing this in India. The costs of doing this are astronomical

00:37:49.280 in the United States, almost $500,000 to a million dollars per person. We're trying to reduce that

00:37:56.460 cost dramatically, 20-fold, perhaps even 50-fold in India using new technologies, etc. We've treated

00:38:02.400 about 11, 12 patients already, and we've just released the data. It looks very good. They're

00:38:08.020 usually used in blood cancers like lymphoma, leukemia, and myeloma. They've not been so

00:38:13.800 successful in solid tumors for reasons that we don't fully understand that we're still trying

00:38:18.760 to understand. But that's what a CAR T-cell is. It's a weaponized T-cell that goes and kills cancer

00:38:24.960 cells in your body. What is the difference? Why is there a 20 to 50-fold reduction in cost doing this

00:38:32.440 in India as opposed to the United States? Because this is, of course, one of the jugular issues with 1.00

00:38:37.760 oncology is marginal treatments. Not that I'm saying CAR T-cell is marginal. It's actually one of the few

00:38:44.040 beacons of success. But cancer is full of marginal treatments, you know, extend median survival by two

00:38:51.140 months at a cost of $100,000. How much of that is just a structural American problem versus people that 0.51

00:38:58.200 are able to go outside of the existing channels of IP? Some of it is a structural American problem

00:39:03.180 and some of it is not. So obviously, the structural American problem is that for reasons that we're

00:39:10.280 trying to still investigate, 90% of drugs, including drugs in the cancer space, fail. And pharmaceutical

00:39:17.240 companies make the argument that they're trying to recoup the R&D costs of those failed drugs with the

00:39:25.500 ones that are successful. Now, that's a complicated and I would say somewhat specious argument because

00:39:30.720 you could say to them, well, why did these drugs fail in the first place? Is it because drugs always

00:39:35.760 fail? Is it because you didn't understand something about the human body that you therefore took this

00:39:41.460 drug all the way to spend millions, perhaps even billions of dollars on the drug? So that's one reason.

00:39:47.980 So that would be the standard argument. The second reason is that CAR T's are intrinsically expensive

00:39:53.680 to make. Their success rates are incredible. So these are not just one month, two months survival.

00:40:00.040 My book begins with the story of Emily Whitehead. She was seven when she was treated with CAR T therapy.

00:40:05.180 She's now 17 or 16, applying to college, completely cured. So you have a situation in which these are

00:40:12.980 miraculous drugs. We've seen people who've had terrible leukemia, essentially eradicated leukemia forever

00:40:20.560 and become cured. The problem is that they're intrinsically hard to make. To weaponize the T

00:40:26.820 cells, you need to make a virus. The virus is expensive to make. It's labor intensive. The quality

00:40:32.200 control that's required is much, much greater than, you know, making aspirin or making any other

00:40:37.660 tablet. And then, of course, growing the T cells, you have to grow them in an incredibly sterile environment

00:40:43.120 where you have to basically put on a hazmat suit to go in. It's called a GMP facility, but it's a

00:40:49.380 highly, highly sterile environment. It has to be monitored. It has to be checked. A single bacteria

00:40:55.220 or a fungal infection in that flask of a T cell will now basically take that entire batch away.

00:41:02.120 You can't give those back. So there are some intrinsic expenses. Now, you asked the question,

00:41:07.660 how can you reduce the cost? Well, we reduce the cost by several ways. One is that we've learned to

00:41:13.440 make the virus in a much cheaper way. We've reduced the cost of the patent burden by essentially really

00:41:22.200 making successful products and not spending millions of dollars on unsuccessful products,

00:41:27.040 so we don't have to recoup all that R&D cost. We've changed the machinery. We've changed the way the

00:41:33.920 cells are harvested. And finally, of course, hospital treatment and therapy in India is much

00:41:38.780 cheaper to start off with. Adding them all together comes to almost a 10-fold to 20-fold reduction in

00:41:45.120 cost. Let's now use another example of gene therapy, which is maybe the harder of the problems.

00:41:52.280 You have a person more like Jesse, where they have a germline mutation that results in a pathology.

00:42:00.000 And the goal is as an adult, let's pick sickle cell anemia as an example. In some ways, sickle cell

00:42:07.900 is so amazing that one single amino acid difference can have such catastrophic consequences on the life

00:42:15.260 of a person. But you want to now just change that. I mean, it's a single amino acid. We know exactly

00:42:20.820 what genes drive that. How does one go about doing that? And where are we in the realm of approaching

00:42:27.120 success there? Fantastic new results in sickle cell anemia published in very major journals and will

00:42:34.720 continue to get published. Ancient disease, as you know, single amino acid mutation. If you inherit

00:42:40.180 two copies, then you get sickle cell anemia, a terrible disease. Your blood cells in low oxygen

00:42:46.340 environments form sickles. They basically clog up. It's like plumbing clogging up. And you get essentially

00:42:52.540 what you might consider micro strokes all over the small blood vessels in your body. Terrible pain

00:42:59.560 associated with it. So the answer would be in gene therapy, what if you could change the mutated gene?

00:43:06.780 So there are two or three approaches that have been so far tried. One is using new technologies,

00:43:13.840 gene editing technologies, to basically change both copies of the gene to now make them into normal. So

00:43:20.040 take out your bone marrow, which is where blood is made, change the gene from the abnormal gene to the

00:43:25.920 normal hemoglobin gene, then re-infuse that back into the patient. So that's a gene correction strategy.

00:43:34.020 There's another strategy which is very attractive and fascinating. And I'll just briefly mention it.

00:43:40.380 So it turns out that the fetus, the human fetus, has a special kind of hemoglobin, which is different

00:43:46.340 from adult hemoglobin. And the reason it's different is that the fetus has to extract oxygen from mom's

00:43:52.780 blood. And mom's blood, by the time it reaches the fetus, has already been depleted of oxygen because

00:43:59.140 it's gone through her body. So this is called fetal hemoglobin. Basically, the fetus has a special form

00:44:04.920 of hemoglobin, the oxygen carrier in blood, that can even extract oxygen out of mom's blood.

00:44:12.000 And so another approach to sickle cell anemia is to forget about the sickle gene problem and basically

00:44:20.440 in an adult somehow reactivate or express or make fetal hemoglobin. In that case, you don't need to

00:44:29.520 correct the gene. You leave the gene as it is. You just make fetal hemoglobin, which is very, very avid

00:44:36.060 as an oxygen delivery machine. And the cells don't sickle anymore because they don't have this

00:44:41.500 oxygen problem. And that too has been successful. There have been several trials now showing that if

00:44:47.060 you activate fetal hemoglobin, you can do that. So just to summarize then, you can either do gene

00:44:52.900 therapy to express the corrected version of the sickling gene. The gene is called beta globin.

00:44:59.060 That has been performed. The second approach is to use gene editing technology to change the gene back

00:45:06.100 to its normal form. And the third approach is to reactivate fetal hemoglobin in adults to essentially

00:45:12.780 correct the hemoglobin defect. And all three of them are in trials. And all three have shown various

00:45:18.420 measures of success. My impression is that during our lifetime, we'll see a cure, a permanent cure for

00:45:24.160 sickle cell anemia. So this dovetails nicely into, I think, a term that most people have heard of,

00:45:30.800 but the details of this are pretty important. And this is the idea of CRISPR. Now, I haven't had

00:45:35.900 Jennifer Doudna on the podcast yet. I would love to at some point. So we don't need to necessarily go

00:45:40.000 into the great depths of CRISPR. But I think some history is probably relevant, especially as it

00:45:45.880 pertains to the topic of our discussion, which is cells, bacteria and viruses, or bacteria as the

00:45:51.180 cells and how they interact with viruses as a way to protect themselves. But I now want to use the

00:45:55.120 story of CRISPR to talk about another tool by which one can impart this type of cell therapy. So

00:46:00.580 So the world of genetics was turned upside down in a very important way by the discoveries of

00:46:08.480 Jennifer Doudna, Emmanuel Charpentier, and several others. I should mention Feng Zhang and George Church.

00:46:15.960 And there's a history of this, which is in the book. For a long time, there was the question,

00:46:23.960 so the human genome is a library. Imagine the human genome as a massive library. If it was

00:46:30.260 printed in normal text, it would contain 80,000 books, a massive encyclopedia, stretching across

00:46:39.280 a massive library. And imagine that you wanted to make a change in one word in that library.

00:46:47.320 You want to take book 61 on shelf 47 and make a change from verbal to herbal in that library.

00:46:56.380 This was a dream of scientists for a long time, and no one could do it. And then Jennifer Doudna,

00:47:03.400 Charpentier, assisted by Feng Zhang and other people, figured out that there was a bacterial system

00:47:10.320 evolved millions of years ago that could make that precise change in one word in that entire library,

00:47:19.740 either deleting that word, in other words, erasing it, simplest change, or potentially changing the word to

00:47:27.120 another new word. It's an incredible genetic revolution. So as we move forward into this new

00:47:36.340 universe, we have the capacity to change the human genome in a deliberative and a processed manner.

00:47:46.140 So just take the example of sickle cell anemia that we gave before. We can change that sickle cell

00:47:53.060 anemia gene to a normal gene by using this technology. We can change a mutant or abnormal cystic fibrosis

00:48:02.740 gene to a normal gene, the normal version or the wild type version using this technology. So it's

00:48:10.300 obviously extraordinarily important. And there are many, many applications of this technology.

00:48:16.820 And it's exciting because we can do things that we couldn't do before involving changing genes to new

00:48:25.820 genes, changing genes to their wild type variants or their more common variants and so forth.

00:48:33.000 So we now have the capacity to do this. We can do this with embryonic cells. We can do this with embryonic stem

00:48:41.920 cells. We can do this with bone marrow cells, T cells, CAR T cells. It's a revolution. And all I can

00:48:49.920 emphasize is the depth and breadth of this revolution because it's enormous.

00:48:56.040 Two follow-up questions. The first is, explain using the library analogy, how this system differs

00:49:02.720 from the approach that was used 20 years ago in the case of Jesse Gelsinger that we described where

00:49:09.300 an adenovirus was used. I mean, what's the difference in scale and elegance between what you just described,

00:49:17.180 which is in the 80,000 books, you can go to one page, one word and make the change versus that other

00:49:23.260 approach. So again, imagine the human genome as a massive library, 80,000 books printed on a page.

00:49:32.600 So the old technology, the technology that was used with Jesse Gelsinger is the technology in which we,

00:49:40.740 I'm using metaphors and analogies here, we would insert a new page into that 80,000 page library.

00:49:49.140 So you would go into the library, 80,000 books around you, and you would take a page and insert

00:49:56.140 a new page, a foreign page into that library. The librarian could come, in this case, the immune

00:50:03.300 response, the T cell or the B cell immune response and come and say, wait a second, that's not a page

00:50:09.560 that belongs. And that's what happened with Jesse Gelsinger and other people, librarian being the human

00:50:14.940 body would come and say, wait a second, you're inserting new pages into a library. That's no

00:50:21.060 good and would prevent that. And it seems to me that it was much harder to know where to put that

00:50:27.320 page. I mean, if you knew a priori, I really want that to be between page 87 and 88, you might

00:50:34.520 accidentally insert it somewhere else, right? Exactly. And the librarian would say, well,

00:50:39.160 why are you putting it into Jennifer Egan's book on the Goon Squad? It doesn't belong there. You've

00:50:46.400 just inserted that new page, the new gene into a place where it doesn't belong. And he or she would

00:50:53.640 say, I don't buy this. I'm not going to let you do that. That's absurd. You're reading along with

00:50:59.980 Chekhov or Egan or whoever. And all of a sudden, you find a new page that's been taped in the virus

00:51:07.200 that's carried in the new gene, the new virus. And you say, well, wait a second, that doesn't

00:51:12.360 belong there. And that was where the technology sat for years and years and years. Then Jennifer

00:51:18.680 Doudna, Charpentier and others discovered a method in which you would do just quite the opposite.

00:51:26.040 You would go into a page and say, listen, I have the right page in the right volume of the right book,

00:51:33.600 and I'm going to change one word. The first kind of word that they could change was just

00:51:39.540 deleting a word. And this was using a viral system called CRISPR, and you could just erase a word.

00:51:47.360 And then more and more research showed that you could change the word. And as I said,

00:51:52.980 you could change the word verbal to herbal by changing a single letter and for the most part,

00:51:57.940 leave the library intact. And if you were a very vigilant librarian, you would say,

00:52:03.960 that's okay. You haven't put in an extra page in Charles Dickens' book. You've actually gone to

00:52:11.240 the right book and changed the right word in the right space, in the right time, from one to another.

00:52:18.620 And that's the subtlety of what CRISPR allows us to do. It allows us to make extraordinarily precise

00:52:26.360 changes in extraordinarily precise ways in a massive library, which would not be possible otherwise.

00:52:35.020 So you alluded to this at the outset of your description, which was you could make changes

00:52:39.420 to an embryo. You could take an embryo and you could make a genetic change, which now has pretty

00:52:47.280 significant consequences because it is now a germline change. This is different than if you made a change

00:52:54.460 in a non-germline cell way down the line. And I guess as things would have it, the first documented

00:53:01.580 example of this created quite a controversy. Maybe briefly tell the story of JK and the CCR5 gene.

00:53:10.460 More importantly, what are the implications of that pretty unethical episode?

00:53:16.120 Again, I would encourage people to read the book, The Song of the Cell,

00:53:19.200 to get all the details about it. But a Chinese scientist, JK Hui, made a somewhat bizarre decision.

00:53:28.680 I'll talk about why that decision was bizarre. There is a gene in the human genome that makes

00:53:37.080 cells resistant to HIV infection. There are many genes, but this is one of them. The Chinese 0.99

00:53:43.840 scientists, scientists in this case, Hye-Joon Kan, decided that he was going to make a change in human

00:53:50.640 embryos with gene editing technology, the technology that I just described, which would make the child

00:53:58.080 of a parent couple in which the man was HIV positive, the woman was HIV negative, and make that change in the

00:54:07.560 embryo. And implant those altered embryos into the mom so that they would be HIV resistant because of 1.00

00:54:16.620 this change. So sounds great on paper. The problem is that their risk, the risk of these children to

00:54:24.220 acquire HIV because they were produced by IVF is basically zero. It cannot get HIV. The sperm doesn't

00:54:32.580 carry HIV. So if you produce a child by this method, you basically have a zero risk of HIV infection.

00:54:41.260 It wasn't medically necessary, right?

00:54:43.280 It wasn't medically necessary. Let me take a step back. I make a very big distinction between

00:54:50.080 disease and desire. Disease is fundamentally linked to suffering. When we talk about disease,

00:54:57.880 we talk about human suffering. When we talk about desire, we talk about the idea or aspiration to

00:55:05.840 ameliorate suffering, even where there's no suffering involved, as far as we can tell. Now,

00:55:12.900 in this case, there was no disease. The children had no risk of disease. They couldn't have any risk of

00:55:19.980 disease. The desire was an entirely scientific desire to create a genetically modified embryo. So in this

00:55:31.160 case, in particular, the desire was that they would create a modified embryo and that his inquiry would be

00:55:37.720 the first in human history to create a human embryo with genetically altered cells. So he went ahead with this

00:55:46.680 project, and he created two girls. We don't know their real names. They've been called Lulu and Nana. And what he obtained was not exactly what he hoped to obtain, which is not that precise erasure of verbal to herbal in a single book in the entire library of 80,000 books.

00:56:12.000 What he obtained was a much cruder version of that. And scientists across the world were concerned about, did he obtain informed consent? Did the parents even understand the language that we're using?

00:56:28.360 Now, remember, because this was an IVF procedure, the risk of these children getting HIV was zero.

00:56:35.200 So again, we come to the question of disease versus desire. They had no disease. The only desire was to create someone who was potentially resistant to HIV infection. So we have this situation, which is very unusual, where desire, the desire to change human embryos, the desire to push the frontiers of science, overwhelms the disease, where there is no disease.

00:57:00.960 And so the scientific world became extraordinarily incensed about the idea that this scientist had crossed the boundary between disease and desire. Now, if this had been some disease that the children had inherited, cystic fibrosis, sickle cell disease, Huntington's disease, some terrible thing that they would encounter in their lifetime, the scientific community would have been much more sanguine about it.

00:57:29.260 But these children, but these children, these twins that were born had a zero risk, zero risk of acquiring HIV from their fathers because the sperm had been watched. Sperm don't get infected with HIV. They had no risk of the disease. So what was left was desire, the desire to be first, the desire to create new human embryos. That's what incensed the scientists and the community of scientists.

00:57:58.180 You know, there's probably no greater example of the relationship between science and philosophy. People might want a little bit of a reminder about what a doctorate degree is formally called, right? A doctor of philosophy. When you think about this question, it becomes kind of difficult.

00:58:16.640 And I think in Walter Isaacson's biography of Jennifer Doudna, in your book, this topic is explored. Where does one draw the line? So, you know, Huntington's disease is a great example in the sense that you have an acquired genetic mutation that is 100% penetrable in a devastating disease that shortens life and leads to immense suffering.

00:58:39.680 Would we find many philosophers of science who would say that it is wrong to alter the embryos of adults who have Huntington's disease or carry that trait, that gene, to prevent it from going to their offspring?

00:58:56.100 Which, by the way, if you play the thought experiment out, would eliminate Huntington's disease altogether because these are germline mutations.

00:59:03.080 Like, how does the scientific and philosophical community merge over questions of that nature?

00:59:07.640 And then, of course, just to tell you, eventually, do we move that further to ApoE4, LPA, other genes that are not as penetrant?

00:59:15.180 Right. So ApoE4 is a risk factor for early Alzheimer's disease, just to give you an example of how devastating it can be for particular people who have combinations of ApoE4 and other genetic mutations that increase their risk for early Alzheimer's disease.

00:59:32.740 I think the scientific community would say, for Huntington's disease, the scientific community would say, listen, this is a devastating disease with a huge penetrance.

00:59:46.340 By penetrance, we mean if you inherit the gene, the chances that you'll have the disease is very high.

00:59:52.300 Sometimes that's not the case, right?

00:59:54.420 So you might inherit a mutation in some gene, whatever it might be, but you might not get the disease.

01:00:00.780 BRCA1 is a good example.

01:00:02.740 You might inherit BRCA1 gene, but you may escape having breast cancer in your lifetime.

01:00:09.820 Huntington's disease has a very high penetrance.

01:00:12.820 So in other words, if you inherit the mutation, the likelihood that you'll have the disease is very high.

01:00:17.960 I think the biomedical community would say that for diseases like Huntington's disease, it's probably worthwhile doing an intervention, whatever that intervention might be.

01:00:29.360 But the biomedical community would say that for, in this case, in HIV, it's not warranted.

01:00:36.260 Yeah, this is obvious.

01:00:37.460 And I think that the biomedical community would say it's not necessary.

01:00:41.740 It's not part of the continuum of disease versus desire.

01:00:46.420 It moves towards desire without moving towards disease.

01:00:50.140 I think the other examples of things on the clearly desire spectrum are pretty obvious, right?

01:00:55.480 Like enhancing intelligence or physical traits like strength, size, etc.

01:01:00.120 Of all of these areas, the one I find most interesting is around mental health.

01:01:06.120 Which is, we understand, for example, autism and schizophrenia have an enormous genetic component.

01:01:13.420 On the surface, it might seem like, hey, wouldn't it be great if fewer people were born with autism and or schizophrenia?

01:01:19.320 But it's really nowhere near that simple, is it?

01:01:21.800 And there's a Pandora's box upon which we have no idea what we could lose as a society

01:01:28.940 if we were to sort of sterilize, quote unquote, some of these conditions.

01:01:34.360 You've obviously touched on this, and I want to come back to mental health.

01:01:37.520 Because in some ways, where we're going to go next in this discussion, I think, is to the last cellular territory, right?

01:01:44.780 The cells of the brain.

01:01:45.840 To me, that's the most complicated cells of the body, in a sense.

01:01:50.760 And of course, this is one area where it's very difficult to appreciate a phenotype under a microscope or in a scanner.

01:01:59.340 Part of it has to do with the complexity of these genes.

01:02:01.720 But how do you think about what might be inevitably questions that society faces around the use of this type of precision gene editing

01:02:11.940 when it comes to genetic conditions of the brain?

01:02:15.560 Well, the brain is the most complex of all organs, and it's important to understand that complexity.

01:02:22.500 What we know about diseases like autism and schizophrenia is that there are, broadly speaking,

01:02:30.740 two kinds of genes in the entire spectrum of genetics that have to do with mental diseases.

01:02:38.740 One kind of gene is what I call a shove gene. 0.66

01:02:42.400 Shove, meaning it pushes you really hard.

01:02:46.980 So think about height.

01:02:48.500 Forget about autism for a second.

01:02:50.440 Height has a strong genetic component.

01:02:53.080 Tall parents tend to produce tall children.

01:02:56.520 Short parents tend to produce shorter children.

01:02:59.140 So we know there's a genetic component to it.

01:03:01.740 Now, there are genes in the spectrum of controlling height that are very powerful shove genes.

01:03:12.820 They shove you in one direction or the other.

01:03:16.160 One example is Marfan syndrome.

01:03:18.740 Marfan syndrome is a genetic disorder, a single gene.

01:03:22.600 One gene, if you inherit copies of that gene, you will likely be extremely tall,

01:03:29.760 and you might have other medical and other complications.

01:03:33.200 But you will be tall for sure.

01:03:35.260 There's a story that Abraham Lincoln may have inherited, the Marfan gene.

01:03:39.360 So that's a shove gene.

01:03:41.720 Those are relatively rare in the human population of very tall people.

01:03:48.380 The more common variant is what I call nudge genes.

01:03:53.840 Nudge versus shove. 0.98

01:03:56.000 Nudge genes move you little by little by little by little by little by little towards increasing height.

01:04:03.460 And there may be hundreds.

01:04:05.880 There may be tens of hundreds of genes that may increase your height little by little by little by little by little

01:04:13.160 until you get 5 feet, 10 inches, 5 feet, 11 inches, 6 feet, et cetera, et cetera.

01:04:19.260 So it's not one gene, but hundreds, if not tens of hundreds.

01:04:24.940 Now, transfer that same idea to mental health.

01:04:29.660 There are certainly genes in the human genome that change your neuron physiology,

01:04:37.000 the physiology of your nerves that are shove genes.

01:04:40.140 In other words, if you inherit them, just like Marfan syndrome, you are likely, much more likely to have mental illness in whatever form it is.

01:04:51.160 They're relatively rare, and they are inherited in families.

01:04:55.540 There's a great book on this written recently about a family that has multiple kids with schizophrenia, et cetera.

01:05:03.420 I think it's called Fallen River Road.

01:05:05.200 If I remember correctly, but most mental illness, just by analogy with height, is not the consequence of this shove phenomenon,

01:05:16.540 but are consequences of what I would call death by a thousand cuts, small nudges that would push you towards depression, schizophrenia, autism, et cetera.

01:05:29.140 And in fact, we haven't even found those genes yet, even though we know they exist.

01:05:34.500 In some cases, we haven't even found those genes yet.

01:05:37.440 So the capacity to change those genes is very limited because the examples that I gave you of gene editing, gene alteration technology,

01:05:49.320 are limited to one gene, two genes, three genes.

01:05:53.520 But it's very, very hard to find a way to change those genes, hundreds, potentially tens of hundreds of genes in the mental health spectrum.

01:06:05.240 So it's not as if we can all of a sudden wake up one morning and say,

01:06:10.080 I'm going to change your mental health or change the mental health of your embryo based on the understanding of our shove genes because it just won't happen. 0.81

01:06:19.460 So let's now dig into this complexity issue around the brain.

01:06:24.960 I've tried to explain this to people and I've never been able to do a great job of it.

01:06:28.180 You do a great job of it in the book describing the mystery.

01:06:32.620 And you came up with a way to describe it that I thought was fantastic, which was,

01:06:37.120 and I want to make sure I'm getting this right, so correct me if I'm wrong.

01:06:40.620 You said there are two types of problems in science.

01:06:43.180 There are the eye in the sandstorm problems versus the sand in the eye problems.

01:06:51.560 And as the cellular biologists and neurobiologists were getting deeper and deeper into the brain,

01:06:57.640 and it really seemed like they had figured out this thing, these axons, the movement of electricity, these action potentials,

01:07:05.840 they were figuring this out, but they had a little piece of sand in their eye.

01:07:10.220 What was that piece of sand?

01:07:11.660 And then, again, feel free to expand on this if I haven't provided an eloquent enough setup,

01:07:16.040 but it was a beautiful description.

01:07:18.480 It's a fanciful description and it's an important distinction and it's a philosophical distinction.

01:07:24.760 The eye in the sandstorm problem is a problem in which you encounter something in medical sciences

01:07:33.000 where the information just doesn't fit.

01:07:36.860 It's being in a sandstorm.

01:07:38.200 And I give the example of when we made the transition in physics between Newtonian physics

01:07:44.180 and quantum mechanics and Einsteinian understanding.

01:07:48.920 So, in other words, you reach a place and all of a sudden everything didn't fit.

01:07:53.480 The bending of light, the presence of relativity, etc.

01:07:58.300 Nothing didn't fit.

01:07:59.040 So, you needed a completely new theory, a new paradigm, a totally shift in paradigmatic thinking.

01:08:07.260 That's the eye in the sandstorm problem.

01:08:09.380 So, in other words, there's sandstorms everywhere and you can't make sense of the real world.

01:08:14.840 That's one kind of problem and I'm interested in those problems.

01:08:19.800 The sand in the eye problem, as I call it, is a different kind of problem.

01:08:24.480 It's when everything fits except one fact.

01:08:28.500 And it's very important to understand that both of those are really interesting

01:08:32.520 because the sand in the eye problem says that our theory is almost right,

01:08:38.460 but it's not right because there's something, a fact, that won't fit.

01:08:42.860 And the particular example I use is neuronal transmission.

01:08:47.680 So, when people discovered neurons in the brain,

01:08:51.360 they figured out, basically by looking at an anatomy,

01:08:55.240 that neurons in the brain, there was a space between them.

01:08:59.780 That nerves weren't just wires.

01:09:03.700 If you were an electrician putting out an electrical situation in an apartment,

01:09:09.080 what you wouldn't do is put spaces between the wires

01:09:13.640 so that all of a sudden that space would become a communication between wires.

01:09:18.940 You'd just hook the whole apartment up.

01:09:20.820 But when people like Ramani Kahal and other scientists figured out how to solve this problem,

01:09:28.620 they understood all of a sudden that nerves have spaces in between them.

01:09:34.140 In fact, they had a name for these spaces.

01:09:37.060 It's called a synapse.

01:09:38.840 That is an eye in the sand problem because you say to yourself,

01:09:43.800 wait a second, if the nervous system is just electrical wires strung together,

01:09:49.280 why would you place a space between two electrical wires?

01:09:54.920 And the solution to that problem turns out to be extraordinarily important for neuroscience

01:09:59.860 because what happens between nerves is that an electrical conduction

01:10:05.380 moves from one end of a nerve to the other.

01:10:08.760 And then, and here's the kicker,

01:10:11.280 it changes from an electrical conduction to a chemical signal between one nerve to another.

01:10:17.560 And that chemical signal re-sparks an electrical conduction.

01:10:23.500 So you're going chemical, electrical, chemical, electrical, chemical, electrical.

01:10:29.400 And you could say what mad person or what evolutionary process would ever devise a system like this?

01:10:37.020 And the answer is, the reason is very important.

01:10:40.700 Because what your nervous system is doing is in that transmission between electrical, chemical, electrical, chemical,

01:10:48.480 what your nervous system is doing is it's putting weights so that in the chemical transmission,

01:10:56.920 an electrical impulse could come down a nerve.

01:10:59.660 But let's say there are 10 nerves or 10 neurons, nerve cells that are impinging on one nerve cell.

01:11:07.740 So you could assign a weight as to how much this one was transmitting versus another one.

01:11:15.200 And by assigning those weights, by assigning those calibrations,

01:11:20.500 you could say one is louder than the other.

01:11:24.020 One is softer than the other.

01:11:27.120 One inhibits the other.

01:11:29.380 And it's those combinations of inhibition, loudness, etc., etc.,

01:11:35.560 that allow profound things like sentience and conversation and consciousness and so forth.

01:11:45.020 The analogy that's very important is this is exactly or similarly to how neural networks work.

01:11:51.580 There are weights put on how one layer of communication communicates with the second layer of communication.

01:11:59.900 In other words, some are louder than others, some are softer than others.

01:12:05.760 Imagine discriminating a dog from a cat.

01:12:09.120 You could say that a very loud signal in that discrimination if the animal happens to bark.

01:12:16.140 You know that for sure that's not a cat.

01:12:18.620 That's a very loud signal.

01:12:20.600 A very soft signal could be the weight of the animal.

01:12:24.680 Some dogs are lighter than cats.

01:12:27.160 A very loud signal could be the way that the snout of an animal is fixed with the head of the animal.

01:12:37.480 Dogs have a particular snout-head combination.

01:12:41.040 Cats have a particular snout-head combination.

01:12:44.060 So by adjusting the weights of these combinations, we think by analogy that this is how the brain can discriminate between dogs and cats.

01:12:54.000 We don't know this for sure because this is an area of science that's still in process.

01:13:00.720 But this is a classic example in the 1950s of the idea that why on earth would you take an electrical signal,

01:13:10.560 convert it to a chemical signal, and then convert it back to a micro-signal?

01:13:14.360 The answer is because if it was just an electrical signal, we'd be a box of wires.

01:13:19.220 And a box of wires without the weight between individual signals between the wires is a useless box

01:13:27.620 because we cannot understand how to construct a learning network between a box of wires,

01:13:37.080 whereas we can understand how we can construct a learning network between electrical and chemical stimulation

01:13:45.560 because we can modulate the strength of that chemical stimulation such that we can really actually learn a process.

01:13:54.280 Another way that I like to explain it is using music, which is the electrical signals that travel down the axon are digital.

01:14:03.440 And maybe because I'm an engineer, I do tend to think in terms of digital versus analog processes.

01:14:09.000 But if you explain that digital means it's either completely on or completely off, there is no modulation.

01:14:15.940 And imagine an orchestra that every instrument could only play at one maximum decibel level or not at all.

01:14:24.120 You couldn't have any modulation of sound.

01:14:26.940 It would be a very awful sounding music.

01:14:29.440 But if now each of those instruments can go up and down and crescendo and decrescendo and modulate,

01:14:36.440 you would now have the analog adjustment of music.

01:14:40.200 That's how we make songs.

01:14:41.840 That's probably a cruder analogy, but I think it also gets at this point, which is how did evolution figure this out?

01:14:49.480 How much trial and error went into producing something so remarkable, so brilliant.

01:14:57.560 Again, you wouldn't think to engineer this system necessarily.

01:15:01.040 Well, I mean, I think the reason evolution figured it out is, again, learning a purely electrical system,

01:15:08.080 which is sort of like saying you're playing some music, but you don't have any modulation.

01:15:13.140 You're listening to a score, and the score has no modulation.

01:15:17.520 So you play everything at the same volume, at the same tempo, at the same time.

01:15:21.840 That's not music.

01:15:23.320 That's not the song of itself.

01:15:25.500 What evolution figured out, and by figured out, I don't want to put an anthropomorphic idea on it,

01:15:31.700 but what evolution converged on is the idea that music has tempo, it has pace.

01:15:40.400 Some pieces are softer, some pieces are louder.

01:15:43.140 And by altering this loudness, softness, as we move along in our neurons,

01:15:51.260 that we can produce not just a mechanical output of the score.

01:15:57.360 And your musical analysis is very interesting because that's what we're producing.

01:16:00.860 We're producing not a mechanical output of the score.

01:16:04.980 We're producing a learned output, a mature output of the score.

01:16:11.620 And that mature output has to do very much with modulation.

01:16:16.640 Some parts are louder.

01:16:18.300 Some parts are softer.

01:16:19.840 Some parts speed up in rhythm.

01:16:22.040 Some parts slow down in rhythm.

01:16:24.100 And that is ultimately the music of the cell, but also the music of the brain.

01:16:30.080 So there's many systems we haven't spoken about, but there's one we would be remiss not to speak about

01:16:35.420 because it's near and dear to both of our hearts.

01:16:37.520 So when you went to Oxford to do your PhD as a Rhodes Scholar, you ended up in a lab where you learned immunology,

01:16:45.580 which of course would come to serve you very well as an oncologist and a hematologist today.

01:16:51.160 I want to talk about a couple of things there.

01:16:52.860 First is you spoke, of course, of your mentor Enzo in the lab.

01:16:56.840 Help us understand what it is that was bestowed on you from an education perspective, from a learning perspective,

01:17:05.460 as a doctoral student that we don't really get in medical school.

01:17:10.020 You would go on to Harvard Medical School.

01:17:12.840 You'd get a great medical education.

01:17:14.540 But I think anybody who spent time in a lab will understand that there are just certain things that can't be taught in a classroom.

01:17:20.660 You have to learn things by being in a lab if that's the language you want to be able to speak.

01:17:26.220 What are your recollections of that period of time, especially in the beginning when presumably the learning curve was very steep

01:17:31.000 and you're drinking from a fire hose and you don't know much of what's going on,

01:17:34.280 but you've committed to this path of becoming a scientist first, a physician second?

01:17:39.000 It's a very different kind of thinking process.

01:17:42.280 I like to make medicines.

01:17:44.620 And when I make medicines, I like to make medicines that are important for human life,

01:17:49.680 hopefully for saving lives.

01:17:51.340 I've talked about some of them.

01:17:52.740 We've spoken in prior podcasts about some of the new medicines that I've been involved in inventing.

01:17:59.660 Textbook knowledge in medicine is important and biology is important

01:18:04.640 because it lays the groundwork and the foundations of what we know and what we understand.

01:18:11.160 But textbook knowledge only gets you so far

01:18:13.220 because when you come into the actual laboratory,

01:18:16.880 you understand that there are things that are predictable,

01:18:20.600 there are things that are not predictable.

01:18:22.320 And then you get into these eye-in-the-sandstorm and sand-in-the-eye problems,

01:18:26.600 which are very important.

01:18:28.600 You learn to recognize failure.

01:18:31.920 You learn to recognize how to troubleshoot your way out of failure.

01:18:36.380 None of this is in a textbook.

01:18:38.700 Open a textbook of biology,

01:18:40.740 any textbook of biochemistry, biology,

01:18:42.940 and try to find me a section on troubleshooting.

01:18:47.840 You won't find one.

01:18:49.520 Troubleshooting your way out of failure

01:18:51.280 is the most standard way that we think about medicine and biology.

01:18:58.660 Run a clinical trial.

01:19:00.600 How do we select a patient?

01:19:03.020 So let's say you're running a phase 1,

01:19:05.760 phase 1, 2B clinical trial.

01:19:08.740 I have six open trials right now.

01:19:11.740 How do you run a clinical trial?

01:19:13.440 Read a textbook.

01:19:14.700 Nothing will tell you about how you select a patient for a clinical trial,

01:19:19.600 how you manage a patient with complications for a clinical trial.

01:19:24.460 There is no information anywhere in that textbook about running that trial.

01:19:31.080 Similarly, run an experiment which will set you up for a clinical trial.

01:19:35.760 There is no information in that textbook about how to troubleshoot,

01:19:40.600 where and how to do that science that allows you to make it into human medicine.

01:19:47.280 What if, for instance, you suddenly find that the medicine that you're working with,

01:19:52.540 you're trying to create, isn't pure, that there's a contamination?

01:19:56.780 How do you remove that contamination?

01:19:59.040 There is no method.

01:20:00.580 You can't find a textbook.

01:20:01.540 And so what you do is you ask your peers who've done this before you,

01:20:06.840 and you say, what did you do?

01:20:08.980 And that's not in a textbook.

01:20:11.480 That's not in any book.

01:20:13.340 That's not in a book that's ever been written.

01:20:15.740 So I wanted to write about that.

01:20:17.820 I wanted to write about that process of learning by doing,

01:20:22.440 learning by being, learning by experiencing.

01:20:27.020 And that's why that whole chapter exists in the book.

01:20:31.040 There is a kind of learning that we do by doing, that we be by being, that we acquire by acquiring,

01:20:40.980 that cannot be found in any book or textbook in the medical sciences, and there's no way around it.

01:20:49.720 There are a couple of really personal things I want to ask you about, some of them for selfish reasons.

01:20:53.920 I want to start with writing.

01:20:55.840 For all the times we've had meals together, I don't know how this hasn't occurred to me to ask you,

01:21:00.540 but how and when did this, and when I call it a gift, I don't want to undermine it, Sid,

01:21:07.280 because I don't want to suggest it doesn't require an obscene amount of hard work.

01:21:11.000 But the reality of it is if I spent the rest of my life writing,

01:21:15.060 I would still write like a child compared to an adult in the way that you write.

01:21:19.320 So at what point in your high school, undergraduate, et cetera,

01:21:24.320 did you realize that you had a brilliant way to write?

01:21:28.320 And I will say this, I think you are hands down the best medical writer.

01:21:32.480 I mean, best writer who happens to write about anything that has to do with science and medicine.

01:21:36.420 I mean, it's outstanding, Sid.

01:21:38.400 Well, thanks for the compliments.

01:21:41.060 You know, writing is not an easy process for me,

01:21:44.500 but it's also a somewhat weird process for me.

01:21:47.800 And by weird, I mean, I throw in everything.

01:21:52.120 In the next book that I write, maybe this conversation that we're having,

01:21:56.180 or some aspect of this conversation, some question that you ask in this conversation,

01:22:01.120 will find its way into the book.

01:22:03.480 I have this policy in which there's nothing that's outside my box.

01:22:08.200 It's all part of the box, all part of the whole story.

01:22:12.380 I find that writing is a way for me to think, a way for me to work through my thoughts.

01:22:21.320 And the analogies and the metaphors and the metaphorical parts of my writing

01:22:26.320 are really not in service of writing.

01:22:32.080 They're in service of making me think.

01:22:33.860 They're in service of making me understand why a certain phenomenon is related to another phenomenon.

01:22:43.680 I draw from history.

01:22:45.260 I draw from mythology, from philosophy, from our conversations, from interviews,

01:22:51.180 and everything goes into a book.

01:22:54.300 And in some ways, I feel as if I had to invent that genre, because it was so siloed.

01:23:03.620 Medical writing was about medicine.

01:23:05.880 It wasn't personal.

01:23:08.160 There was sharp distinctions between memoir and case histories.

01:23:13.860 There were sharp distinctions between deep history and an interview or journalistic writing.

01:23:20.580 And I said to myself, these distinctions are arbitrary.

01:23:24.320 They only exist to serve a kind of secondary purpose.

01:23:28.540 Why not erase all of them and make a new kind of writing in medicine or in life?

01:23:34.520 Because the most important thing that I think people told me about medical writing was like,

01:23:41.560 when people read writing about medicine, they want to enter your cosmos.

01:23:46.500 They want to enter your world.

01:23:47.840 They want to know what it's like to be like you.

01:23:51.540 And so I said, okay, I'll show them.

01:23:53.560 What is it like to be like me?

01:23:55.240 Well, it's like to experience absolutely intense exhilaration when a clinical trial is successful.

01:24:04.480 Absolute depths of depression and crisis when a clinical trial fails.

01:24:10.640 Absolute anticipation, absolute apprehension, absolute admiration for people on whose shoulders

01:24:18.880 I stand.

01:24:20.240 That's what it's like to be like me.

01:24:22.540 And when people said to me, show me your world, I said, okay, I'll show you my world,

01:24:28.340 but I'll show you my world in a way that's like to be like me.

01:24:32.420 What is it like to be like me?

01:24:33.760 I am like you.

01:24:35.100 I have terrible days.

01:24:37.680 I have very good days.

01:24:39.720 I have exhilarating days.

01:24:41.900 I make inventions.

01:24:44.120 Those inventions work.

01:24:45.740 Some of them don't work.

01:24:47.320 And all of it is wonderful and terrifying.

01:24:51.480 At the same time, I want to bring you into that.

01:24:54.060 And that means I will combine memoir, journalistic writing, traveling writing, philosophy, mythology,

01:25:03.480 everything.

01:25:04.120 I'll throw everything in there so that you understand what it's like to be like me.

01:25:09.700 There are two things you talked about in the book, Sid, that were completely unconnected,

01:25:13.840 but immediately in my mind were connected.

01:25:15.740 And it probably has to do with my own world.

01:25:18.760 As you know, Sid, I think a lot about the end of life.

01:25:22.700 I think a lot about how we can delay and push off the end of life.

01:25:28.120 And one of the things that I think a lot about is how quickly life can vanish in a person

01:25:33.140 when they fall.

01:25:34.680 An older person, I don't mean a 10-year-old.

01:25:37.100 And these two things that you write about, and again, totally different parts of the book.

01:25:41.240 You talk very openly about your own depression that really kicked in a year after your father's

01:25:46.040 death, which resulted from a fall.

01:25:48.220 And near the very end of the book, you talk about the end of Virchow's life, which I was not

01:25:52.160 aware of how Virchow died.

01:25:54.500 I was completely unaware of that, that he ultimately died as a result of a fall and a broken femur.

01:26:00.000 And within less than six months, he was dead, which is unfortunately far more common than

01:26:05.960 people realize.

01:26:07.080 I mean, it is the leading cause of accidental death.

01:26:10.800 And the mortality, as you know, Sid, from a person over the age of 65, if a person at that

01:26:17.480 age or above falls and breaks their femur, depending on the study, it's anywhere from

01:26:22.180 10 to 30% mortality at 12 months.

01:26:24.960 And you do a very good job of explaining the why, because a lot of people, when confronted

01:26:30.400 with that fact, simply can't understand it.

01:26:33.740 And I was again confronted by it just two days ago when the swim coach of Stanford, while

01:26:39.440 I was there, of course, I didn't swim at Stanford, but many of my friends did and I knew him and

01:26:43.540 I got to know him later after he had retired.

01:26:46.320 And he fell two weeks ago, broke his hip, and two weeks later, he's dead.

01:26:51.620 Never really recovered from the surgery.

01:26:53.620 That's a very extreme example.

01:26:55.700 It's interesting to me, but what I couldn't believe was how you tied it back to this cell,

01:26:59.940 which was here we have one of these giants of cellular biology who falls and dies, but

01:27:06.540 it's actually the result of a cellular process.

01:27:09.540 It starts with the osteoclast and the osteoblast and the matrix of the hip, and ultimately it leads

01:27:15.360 to organ failure.

01:27:16.920 That's not a leap that I think is easy to make.

01:27:19.760 It's not obvious.

01:27:21.420 It's obvious when you think about Burkow's own idea that the body is a citizenship.

01:27:27.120 Yeah, well said.

01:27:29.540 And the citizenship falls when one part of the citizenship falls.

01:27:34.360 Imagine a citizenship in any capacity.

01:27:37.640 All of a sudden, your Bureau of Transportation decides to take a leave for 20 days.

01:27:44.120 The trains in New York City stop running.

01:27:47.400 Therefore, people can't go to work.

01:27:49.660 And the economy collapses.

01:27:52.600 The economy collapses.

01:27:53.600 The economy collapses.

01:27:54.540 And all of a sudden, people who are dependent on small changes in their lifetimes, wage workers,

01:28:03.080 collapse.

01:28:03.540 And then the entire system, the network of systems collapses, all because the Department of Transportation

01:28:10.820 closed down for two days.

01:28:12.060 That's what happens in the human body.

01:28:14.340 That's the liability, in some ways, of multicellular existence.

01:28:19.260 There are many advantages.

01:28:21.120 We talked about multicellular existence as advantages.

01:28:24.660 But there are also liabilities because you depend on your pancreas for insulin.

01:28:29.360 Your brain doesn't make insulin.

01:28:31.240 You depend on your brain for sensuous and consciousness.

01:28:34.600 You depend on your muscles for movement.

01:28:36.600 Your brain can't produce movement without muscles.

01:28:38.720 So there's a citizenship that bodies develop and have developed with each other so that

01:28:45.160 we, together, perform as organisms.

01:28:48.620 And if you take away one piece of that, a broken bone, it pings into a capacity not to

01:28:55.500 move.

01:28:56.340 The capacity not to move wastes your muscles.

01:28:59.140 Your wasted muscles then communicate with the rest of your body.

01:29:02.580 You and I have talked about hormonal systems before that conduct hormones between wasted

01:29:08.220 muscles, et cetera.

01:29:09.400 And then this pinged system then goes on and on and on until you end up with, as I said.

01:29:15.580 Say it again, another personal question.

01:29:17.680 How much did you weigh the pros and cons of writing about such personal matters as your

01:29:26.600 own depression?

01:29:27.600 We do still live in a world where it's not entirely clear to me why we view depression

01:29:34.100 different from hypertension.

01:29:36.160 For example, if a person says, I have hyperlipidemia and I take 10 milligrams of Lipitor a day, I

01:29:41.920 don't think anybody bats an eye.

01:29:43.760 But if somebody says, I'm really struggling with depression and I take an antidepressant,

01:29:49.200 it just has a different valence to it for some reason.

01:29:53.080 Again, I don't know why that is.

01:29:54.620 I really don't.

01:29:55.460 But in the presence of that knowledge, you still chose to talk about this.

01:30:01.140 Why?

01:30:02.480 Well, Peter, it was a very conscious choice.

01:30:04.480 It was not unconscious.

01:30:05.860 I talked to my family about it and I made the choice after that conversation.

01:30:10.100 I agree with you.

01:30:11.480 I think that depression can be what's called an organic disorder, a disorder in mood-regulating

01:30:19.060 neurons in your brain.

01:30:20.220 Just like type 1 diabetes is an organic disorder, a disorder in the inability of pancreatic beta

01:30:27.780 cells to secrete insulin.

01:30:29.000 The reason it's different, I think, is that we associate a kind of victimhood to mental disorders.

01:30:38.260 And that kind of victimhood is punitive.

01:30:42.140 It blames victims for being victims in a way that, you know, you don't say that, oh, you know,

01:30:48.080 you're hypertensive because you have genetics or behaviors, et cetera, et cetera, that are

01:30:55.680 related to your hypertension.

01:30:57.940 But depression and mental disorders, grief, depression, and perhaps even more complex disorders,

01:31:05.520 schizophrenia, have a sense of blaming the victim.

01:31:09.600 And the victim being the person who's experiencing the disorder.

01:31:14.840 That victimhood, I think, has to do with the idea that the brain is separate from the rest

01:31:19.260 of the body.

01:31:20.280 It's a special organ.

01:31:22.120 And yes, of course, it's a special organ.

01:31:23.900 There's no doubt about that.

01:31:25.220 But on the other hand, it's also an organ that has physiology, just like your pancreas

01:31:30.040 has physiology, just like your heart has physiology.

01:31:33.360 And so what I wanted to get away from is this idea of special victimhood and talk about the

01:31:40.840 brain as a cellular cluster, which is in some ways just a cellular cluster like the pancreas

01:31:49.140 or the heart or the liver is a cluster and thereby remove this or defend or even challenge this

01:31:59.660 idea of victimhood and responsibility, because most people who experience severe clinical

01:32:07.580 depression experience it as a consequence of, of course, of environmental and emotional

01:32:14.340 stimulation, the grief of dying, the grief of their situation.

01:32:20.080 But there are neuronal or nervous nerve cells and nerve cell circuits that push them.

01:32:29.660 In biochemical and chemical ways towards the state in which they cannot function.

01:32:36.380 And I want to highlight that that absence of function, if Virka was alive today, Virka would

01:32:43.800 say that absence of function or that dysfunction is not dissimilar to a person who has a failing

01:32:52.200 heart or a failing liver, because that function is a dysfunction of mood regulating circuits and neurons

01:33:02.220 in the brain, just as type 1 diabetes is a dysfunction of insulin regulating cells in the pancreas.

01:33:11.080 And that idea, again, is, I think, very important and I think radical in this book and in all my books.

01:33:21.260 I agree with you completely. I think it is entirely radical and it's, I think, very difficult.

01:33:27.080 You know, I spoke about this with Carl Deseroth. If you haven't read his book, by the way, it's a

01:33:31.140 fantastic book as well.

01:33:32.380 I have read his book. It's incredible.

01:33:34.140 And Carl was a classmate of mine in medical school and he was equally brilliant then as

01:33:39.360 he is now. But he talks about this idea, right? Which is, it's this entire field of medicine,

01:33:44.500 I'm referring to psychiatry, for which we have not one biomarker, for which we have not one

01:33:50.060 radiographic finding that lends itself to a diagnosis. And so in the example of that failing

01:33:56.200 heart and that failing liver, we have a menu of things to aid in the diagnosis. In fact, it's

01:34:02.300 much easier to make that diagnosis today than when William Osler had to make the diagnosis

01:34:07.860 125 years ago. I mean, today, a medical student can diagnose a failing heart and a failing liver,

01:34:15.280 given enough data. And yet there's still this black box inside of our brains in some ways. And I find it

01:34:23.400 very interesting and I can't help but wonder where we will be in 20 years. Like when I think about

01:34:30.760 oncology today, and I think about what the wish for oncology is in 20 years, and I think about

01:34:36.940 psychiatry today and psychiatry in 20 years, I feel like there's even more potential in psychiatry.

01:34:42.500 And of course, I think the potential in oncology is enormous.

01:34:46.080 I think you've hit the nail on the head, which is to say that biomarkers will help and are always

01:34:51.920 helpful. But ultimately, it's a clinical decision. I always tell people who haven't been in clinical

01:34:59.420 medicine. When you see depression, you know depression. You know that this person has a

01:35:04.960 dysfunction of the neural circuits that regulate mood, just like a patient with type 1 diabetes

01:35:10.880 has a dysfunction in the cells that secret insulin. And even if there are no biomarkers,

01:35:17.020 you know it. This is what humans can see about other humans. There is a disproportionality

01:35:24.040 or a disconnection between the level of grief that a person experiences and the level of grief that

01:35:33.860 persists ennui, the level of psychomotor inability to move that a person experiences when they're

01:35:42.040 clinically depressed. So I think that even in the absence of biomarkers, I think there is a new age

01:35:49.480 that is coming and a respect, I think, for the autonomy of patients who experience neurological

01:35:56.840 and psychiatric diseases. And I think, as you've said before, Deseroth writes about them

01:36:02.060 very carefully and very thoughtfully. There are many people, Andrew Solomon has written about all of

01:36:08.040 this. And I think it's very important because we could find therapies for these. Some of them may be

01:36:13.720 related to things that you and I are very interested in, like alterations in diets, alterations in

01:36:21.080 diets plus medicines, alterations in human physiology that could reset brain circuits,

01:36:28.020 electrical stimulation, as Helen Mayberg and others have been doing. And to treat the problem as if it

01:36:34.940 was just a problem that is sort of a heavy phenomenon is to minimize what the problem is.

01:36:41.920 Sid, there's so much more I wanted to talk with you about, but not surprisingly, we've gone pretty

01:36:47.760 deep in a few things and there are topics like the entire immune system, the epigenetic phenomenon and

01:36:55.760 how we get into cellular reprogramming and Yamanaka factors. I mean, there's, we got through about half

01:37:01.000 of what I wanted to talk about. So I think the only reasonable thing to do here is to say, once the book

01:37:05.500 tour is behind you, once we've both got a little bit more breathing room, we should sit down again and do

01:37:10.920 part three, where we talk about some of these other factors. You have a wonderful way of explaining

01:37:15.800 complicated ideas. And frankly, I think perhaps the single most important thing I wanted to talk

01:37:20.640 about today, which was to bring all of this around the future of science and the culture of anti-science

01:37:27.520 that is propagating. I hesitate to not touch on that now, but I don't think we could do it justice

01:37:32.700 with a glib and short discussion. And I'd, with your blessing, like to postpone that as yet another

01:37:37.280 topic we can explore hopefully in 2023. Would love to. And good luck. I love your podcast and I love being on it.

01:37:45.160 So. Well, thank you, Sid. And congratulations again on another masterpiece. And I'm looking forward to

01:37:50.680 helping to spread the word so that many more people experience the joy of reading the word. Thank you, Sid.

01:37:55.360 Thank you for listening to this week's episode of The Drive. If you're interested in diving deeper

01:38:00.340 into any topics we discuss, we've created a membership program that allows us to bring you

01:38:04.720 more in-depth exclusive content without relying on paid ads. It's our goal to ensure members get back

01:38:10.500 much more than the price of the subscription. Now to that end, membership benefits include a bunch of

01:38:15.840 things. One, totally kick-ass comprehensive podcast show notes that detail every topic, paper,

01:38:21.420 person thing we discuss on each episode. The word on the street is nobody's show notes rival these

01:38:26.860 monthly AMA episodes or ask me anything episodes, hearing these episodes completely access to our

01:38:33.500 private podcast feed that allows you to hear everything without having to listen to spiels like 1.00

01:38:38.400 this. The qualies, which are a super short podcast that we release every Tuesday through Friday,

01:38:44.280 highlighting the best questions, topics, and tactics discussed on previous episodes of The Drive.

01:38:48.540 This is a great way to catch up on previous episodes without having to go back and necessarily

01:38:53.400 listen to everyone. Steep discounts on products that I believe in, but for which I'm not getting

01:38:58.960 paid to endorse, and a whole bunch of other benefits that we continue to trickle in as time goes on.

01:39:04.480 If you want to learn more and access these member-only benefits, you can head over to

01:39:07.860 peteratiamd.com forward slash subscribe. You can find me on Twitter, Instagram, and Facebook,

01:39:14.620 all with the ID peteratiamd. You can also leave us a review on Apple Podcasts or whatever podcast

01:39:21.420 player you listen on. This podcast is for general informational purposes only and does not constitute

01:39:26.980 the practice of medicine, nursing, or other professional healthcare services, including

01:39:31.520 the giving of medical advice. No doctor-patient relationship is formed. The use of this information

01:39:37.380 and the materials linked to this podcast is at the user's own risk. The content on this podcast

01:39:43.260 is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users

01:39:49.680 should not disregard or delay in obtaining medical advice from any medical condition they have,

01:39:55.960 and they should seek the assistance of their healthcare professionals for any such conditions.

01:40:01.460 Finally, I take conflicts of interest very seriously. For all of my disclosures and the companies I invest

01:40:06.680 in or advise, please visit peteratiamd.com forward slash about where I keep an up-to-date and active list

01:40:15.260 of such companies.

01:40:36.680 Thank you.

01:40:45.820 You

The Peter Attia Drive - February 27, 2023

#244 ‒ The history of the cell, cell therapy, gene therapy, and more ｜ Siddhartha Mukherjee

Episode Stats

Summary

Transcript